Faculty Research Profile

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My research is focused on the discovery of new anticancer drugs with a primary interest in novel anti-mitotic agents. Drugs that interrupt mitosis are some of the most efficient anticancer agents in use today for a wide variety of adult and pediatric cancers, but innate and acquired drug resistance limits the use of most of these drugs. I?ve been using a cell-based screening assay for the past 19 years to identify new microtubule disrupting agents in crude marine and terrestrial natural products, chemical libraries and directed chemical syntheses. A highlight of our work is that all of the classes we?ve identified thus far can circumvent a clinically relevant mechanism of drug resistance, the expression of the drug efflux pump, P-glycoprotein. The first group of compounds that I discovered in this assay, the cryptophycins, advanced to Phase I clinical trials, but due to toxicities, did not advance. Other analogs were being considered for clinical development. We then identified two new classes of microtubule stabilizers, the laulimalides from a marine sponge and the taccalonolides from a tropical plant. The taccalonolides are unique as compared to other microtubule stabilizers in that they do not bind directly to tubulin. We are investigating the cellular binding site by a variety of methods including in yeast and c. elegans models and direct labeling of the compound with fluorescent or biotinylated labels. My laboratory is also investigating the signaling pathways initiated by the taccalonolides and how they differ from clinically used microtubule stabilizers including Taxol. A second project ongoing in the laboratory is aimed at identifying the molecular pharmacology of diverse microtubule stabilizers including Taxol, epothilone B and lauliamalide. We are investigating the cellular signaling pathways leading from inhibition of microtubule dynamics to the initiation of aberrant multipolar mitotic spindles. Identification of these signaling pathways will allow for upstream targeting and may alleviate a major dose-limiting toxicity of microtubule-targeting agents, peripheral neuropathy. In addition to my work on microtubule stabilizers we are investigating several new classes of microtubule depolymerizing agents we discovered. To date no agent that binds within the colchicine-binding site is approved for use against cancer. We are working with multiple compounds that bind within this binding site to identify lead compounds with good efficacy and low toxicity. We evaluate these compounds for antiangiogenic or antivascular actions, because colchicine-site binding agents can exhibit either effect. Combinations of antivascular compounds that attack a tumor from the inside out, by rapidly destroying existing tumor vasculature with an antiangiogenic compound that prevents new vessel formation may provide for effective cancer control. These studies are ongoing.
In addition to our work on anti-mitotic agents we are also purifying cytotoxic

Federal

The goals of this project are to identify new targeted therapies for the treatment of the distinct subtypes of triple negative breast cancer.

Funding Agency

NIH/NCI

Title

Cancer Center Support Grant

Status

Active

Period

8/2009 - 8/2019

Role

Co-Investigator

Grant Detail

The Cancer Center support grant provides infrastructure support for the Scientific Program and Shared Resources of the CTRC at UTHSCSA. Only 63 cancer centers nationally are NCI-designated Centers and the CTRC is one of 3 in the state of Texas to have this designation.

Funding Agency

NIH/NIGMS

Title

Sourcing bioactive secondary metabolites from Great Lakes Fungi

Status

Active

Period

7/2014 - 4/2019

Role

Co-Principal Investigator

Grant Detail

This project will utilize new and unique natural products made by fungi derived from the Great Lakes as a resource for generating new bioactive compounds to treat childhood cancers.

Funding Agency

NIH/NCI

Title

Taccalonolides: Mechanisms of Action and Cellular Resistance

Status

Active

Period

9/2006 - 6/2018

Role

Principal Investigator

Grant Detail

The goals of this effort are to identify the molecular mechanisms of action of the taccalonolides, and to identify structure activity relationships of this new class of microtubule stabilizing agents.

Funding Agency

NIH/NCI

Title

Taccalonolides: Mechanisms of Action and Cellular Resistance

Status

Active

Period

4/2006 - 6/2017

Role

Principal Investigator

Grant Detail

The goals of this effort are to identify the molecular mechanisms of action of the taccalonolides and to identify structure activity relationships of this class of microtubule stabilizing agents. The overall goal of this research project is to identify the cellular mechanisms of action and resistance of the taccalonolides, novel cytotoxic steroids with a unique mechanism of action. The taccalonolides are a new class of microtubule stabilizers and they are the first microtubules stabilizers identified that have Taxol-like effects in cells without binding to tubulin. They may have potential for the treatment of cancer. These studies are expected to identify new targets for stabilizing microtubules that lead to antitumor effects and will identify new drug targets. The information gained from these studies will also identify the signaling pathways invoked by chemically and biologically diverse microtubule stabilizers to initiate mitotic arrest and subsequent apoptosis. These studies will lead to the identification of new therapeutic targets for cancer that could provide the anticancer efficacy of the taxanes with the ability to circumvent taxane drug resistance including tubulin-mediated taxane toxicity. By comparing the activities of the taccalonolides with Taxol and discodermolide we will gain an understanding of the advantages of each stabilizer and how they can best be used to treat human cancers. The first goal of this effort is to identify the cellular binding site of the taccalonolides. We will test the hypothesis that the taccalonolides bind to and inhibit an intrinsic cellular microtubule destabilizing factor resulting in microtubule stabilization. A second goal is to elucidate the mechanisms by which the taccalonolides interrupt mitotic signaling leading to mitotic arrest and apoptosis. We will test the hypothesis that the taccalonolides inhibit Aurora A expression and activity. Drug resistance is an important problem in the treatment of cancer. We

Funding Agency

NIH/NCI

Title

Water-soluble Antimitotics that Circumvent Tumore Resistence

Status

Active

Period

6/2011 - 5/2016

Role

Co-Principal Investigator

Grant Detail

The goals are to discover new tubulin-binding antimitotic drugs

Private

Funding Agency

Eisai, Inc.

Title

Elucidation of the effects of eribulin on cellular signaling pathways and how the effects differ from those initiated by other microtubule targeting agents

Status

Active

Period

5/2016 - 5/2018

Role

Principal Investigator

Grant Detail

The project will evaluate how the approved drug eribulin acts in interphase cells to inhibit cellular signaling pathways.

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